Ultrasmall Iron Oxide Particles Research Articles

Real‐time 3D MRI of contrast agents in whole living mice

A specific mouse whole body coil and a dedicated gradient system at 4.7 T were coupled with an ultra-fast 3D gradient echo MRI and keyhole reconstruction technique to obtain 3D whole-body dynamic T(1)-weighted or T(2)*-weighted imaging. The technique was used to visualize the real-time distribution of non-targeting T(1) and T(2)* contrast agent (CA) in a glioma-bearing mouse model. T(1) dynamic contrast-enhancement imaging was performed with a fast imaging with steady-state precession sequence [echo time/repetition time (TE/TR), 1.32/3.7 ms] before and after CA injection (Gd-DOTA and BSA-Gd-DOTA) for 21 min. The temporal resolution was 1 image/6.5 s. T(2)* imaging (TE/TR, 4/8 ms) was performed before and after iron-based (small and ultra-small particles of iron oxide) CA injection for 45 min. The temporal resolution was 1 image/14 s. Signal-to-noise ratio curves were determined in various mouse organs. The whole-body coil and gradient systems made it possible to acquire data with sufficient and homogeneous signal-to-noise ratio on the whole animal. The spatial resolution allowed adequate depiction of the major organs, blood vessels and brain glioma. The distribution and the time-course of T(1) and T(2)* contrasts upon contrast agent injection were also assessed. 3D whole-body mouse MRI is feasible at high spatial resolution in movie mode and can be applied successfully to visualize real-time contrast agent distribution. This method should be effective in future preclinical molecular imaging studies.

Reduction in Arterial Wall Strain With Aggressive Lipid-Lowering Therapy in Patients With Carotid Artery Disease

Inflammation and biomechanical factors have been associated with the development of vulnerable atherosclerotic plaques. Lipid-lowering therapy has been shown to be effective in stabilizing them by reducing plaque inflammation. Its effect on arterial wall strain, however, remains unknown. The aim of the present study was to investigate the role of high- and low-dose lipid-lowering therapy using an HMG-CoA reductase inhibitor, atorvastatin, on arterial wall strain. Forty patients with carotid stenosis >40% were successfully followed up during the Atorvastatin Therapy: Effects on Reduction Of Macrophage Activity (ATHEROMA; ISRCTN64894118) Trial. All patients had plaque inflammation as shown by intraplaque accumulation of ultrasmall super paramagnetic particles of iron oxide on magnetic resonance imaging at baseline. Structural analysis was performed and change of strain was compared between high- and low-dose statin at 0 and 12 weeks. There was no significant difference in strain between the 2 groups at baseline (P = 0.6). At 12 weeks, the maximum strain was significantly lower in the 80-mg group than in the 10-mg group (0.0850.033 vs. 0.1690.084; P = 0.001). A significant reduction (26%) of maximum strain was observed in the 80-mg group at 12 weeks (0.0180.02; P = 0.01). Aggressive lipid-lowering therapy is associated with a significant reduction in arterial wall strain. The reduction in biomechanical strain may be associated with reductions in plaque inflammatory burden.

In vitro biomedical applications of functionalized iron oxide nanoparticles, including those not related to magnetic properties

Superparamagnetic iron oxide nanoparticles (SPION) are very promising contrast media, especially for molecular imaging, due to their superior NMR efficacy. They even have wider biomedical applications such as in drug and gene delivery, tissue engineering and bioseparation, or as sensitive biological nanosensors. By coupling them to affinity ligands, SPION can bind to drugs, proteins, enzymes, antibodies or nucleotides. For in vitro biomedical applications, the detection of molecular interaction is possible by using a diversity of systems capable of sensing the magnetic properties of these materials. The goal of the present work was to develop and validate various in vitro biomedical applications of ultrasmall superparamagnetic particles of iron oxide (USPIO), including some that are not related to their magnetic properties. USPIO coated with dextran, starch or bisphosphonate exposing carboxylate groups were synthesized and some of them were functionalized by conjugating various biomolecules, such as biotin, streptavidin and apoptosis, or VCAM-1 specific peptides. The in vitro biomedical applications assessed in the present work included: (1) the relaxometric measurement of antibody concentration, cell receptor expression, molecular interaction, and enzymatic activity in aqueous suspensions; (2) MRI visualization of cells and detection of molecular interaction in an ELISA system; (3) ELISA applications of USPIO derivatives; and (4) detection of specific biomolecules by histochemistry. Our results confirm that rapid and simple in vitro detection of a diversity of functionalized SPION with relevance in medicine is possible by the existing NMR techniques and by chemical staining reactions. The protocols can be applied to minimally prepared biological samples (e.g. whole blood, blood plasma or serum, cell suspensions, biopsies, histological preparations, etc.), and often do not need complicated systems of signal amplification. The use of SPION labeled compounds could furthermore contribute to cost reductions in the diagnosis and in patient care.

Assessment of Age Modulated Vascular Inflammation in ApoE−/− Mice by USPIO-Enhanced Magnetic Resonance Imaging

Inflammation within atherosclerotic lesions increases the risk for plaque rupture and thrombosis. A functional approach to plaque analysis is the intravenous administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) that enables visualization of macrophages residing in the plaques. In this study, we sought to characterize the age-related inflammatory status associated with atherosclerosis lesion progression in ApoE mice using USPIO-enhanced magnetic resonance imaging (MRI). A total of 24 ApoE mice were divided in 4 groups (N = 6) and were given a high cholesterol diet from 6 weeks of age to the end of the protocol. One group per MR time point was investigated at 10, 16, 24, and 34 weeks of age. Each MR examination was performed on a 4.7 T scanner and consisted of baseline and 48 hours post-USPIO administration imaging sessions. P904, a USPIO contrast agent (Guerbet, Paris, France) with a potential for plaque macrophage targeting, was used.Vessel wall area measurements were performed on high resolution spin echo transverse images. Multi-echo gradient-echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. A one-way analysis of variance was performed to characterize the temporal variation of vessel wall area, susceptibility artifact area, baseline, and post-USPIO T2* values. MR measurements were correlated with the histologic findings. A significant increase was found in the aortic wall area from 1.4 ± 0.2 at 10 weeks to 2.0 ± 0.3 mm at 34 weeks of age (P < 0.05). Concerning the post-USPIO MRI, signal loss regions, with patterns spanning from focal to the complete disappearance of the vessel wall, were observed on all postcontrast images. A significant increase in the size of the susceptibility artifact was observed from 0.5 ± 0.2 to 2.4 ± 1.0 at 24 weeks (P < 0.05) and to 2.0 ± 0.9 mm at 34 weeks (P < 0.05).The T2* values calculated on the 48 hours post-USPIO images were shorter compared with baseline. The decrease was 34% ± 16% at 10 weeks, 57% ± 11% at 16 weeks, 57% ± 16% at 24 weeks, and 48% ± 13% at 34 weeks.The Pearson's correlation test between measurement of aortic wall area performed on both MR images and histologic analysis showed a statistically significant correlation (r = 0.695 and P < 0.05). A correlation was also obtained between the signal loss area and the macrophages covered area (r = 0.68 and P < 0.05). This study demonstrated the feasibility of USPIO-enhanced MRI in assessing the inflammatory status related to the temporal progression of the atherosclerosis plaque in ApoE transgenic mice model of atherosclerosis. In our experimental conditions, the vascular inflammation peak, for the ApoE mice feeding high-fat/high-cholesterol diet is measured between 16 and 24 weeks of age.

Imaging of the vulnerable carotid plaque: Biological targeting of inflammation using ultrasmall superparamagnetic particles of iron oxide (USPIO) and MRI

Imaging of the vulnerable carotid plaque: Biological targeting of inflammation using ultrasmall superparamagnetic particles of iron oxide (USPIO) and MRI

Functional connectivity in blood oxygenation level‐dependent and cerebral blood volume‐weighted resting state functional magnetic resonance imaging in the rat brain

To directly compare functional connectivity and spatiotemporal dynamics acquired with blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV)-weighted functional magnetic resonance imaging (fMRI) in anesthetized rats. A series of BOLD images were acquired in 10 rats followed by CBV-weighted images created by injection of ultrasmall iron oxide particles. Functional connectivity, spectral information, and spatiotemporal dynamics were compared for the BOLD and CBV-weighted resting state scans. BOLD scans exhibited higher cross-correlation values compared to CBV-weighted scans, but the spatial patterns of correlation were similar. The BOLD spectrum contains power evenly distributed throughout the low-frequency range while the CBV power spectrum exhibited a high power peak localized to approximately 0.2 Hz. Both BOLD and CBV resting state scans showed similar propagating waves of activity along the cortex from the SII toward MI; however, these waves were detected more often in BOLD scans than in CBV scans. While the power spectrum of the CBV signal is different from that of the BOLD signal, both connectivity maps and spatiotemporal dynamics are similar for the two modalities. Further experiments should address the relationship between spontaneous neural activity, local changes in metabolism, and hemodynamic fluctuations to elucidate the origins of the BOLD and CBV signals.

BAS/BSCR19 Visualising inflamed atherosclerotic plaques: molecular imaging using MRI and targeted ultrasmall superparamagnetic particles of iron oxide

IntroductionThere are currently no clinical imaging techniques available to assess the degree of inflammation associated with atherosclerotic plaques. This study aims at visualising and characterising atherosclerosis using targeted ultrasmall superparamagnetic...

Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis

Signal loss observed in the brain by MRI following the administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) has been correlated with immune cell activity in inflammatory areas during multiple sclerosis. Uptake of USPIO by circulating monocytes and their migration towards inflammatory areas have been considered as the most important mechanism for USPIO uptake by the brain parenchyma. However, the involvement of a damaged blood-brain barrier is also debated as a possible mechanism for cerebral USPIO uptake. Compared with these uptake-associated issues, little is known about the clearance of USPIO from the brain. The acute uptake and chronic clearance of USPIO in the brain were therefore studied with MRI in an animal model of multiple sclerosis. Lewis Hannover rats with acute experimental autoimmune encephalomyelitis received a single intravenous injection of USPIO (300 µmol Fe/kg), and repetitive MRI of the brain and cervical lymph nodes, a possible drainage pathway, was performed. USPIO were detected in the brain within 1 h after injection independent of the severity of experimental autoimmune encephalomyelitis, and histological analysis revealed extracellular iron clusters colocalising with a leaky blood-brain barrier. Loss of signal was not present 72 h after USPIO injection, irrespective of the disease state. MR images of cervical lymph nodes showed USPIO accumulation at 24 h after administration, which stabilised at 72 h. Histological analyses revealed that USPIO accumulated in infiltrated macrophages in the medulla and subcapsular sinus. The current study demonstrates that USPIO enter the central nervous system directly after administration, pointing to the involvement of a damaged blood-brain barrier in the appearance of USPIO-associated MR abnormalities. Furthermore, a possible role of the cervical lymph nodes as a drainage pathway of USPIO is suggested. These data shed new light on the use of USPIO in neuroinflammatory diseases, identifying USPIO as a marker for both cellular infiltration and blood-brain barrier damage.

NMR-based metabonomic analyses of the effects of ultrasmall superparamagnetic particles of iron oxide (USPIO) on macrophage metabolism

The metabonomic changes in murine RAW264.7 macrophage-like cell line induced by ultrasmall superparamagnetic particles of iron oxides (USPIO) have been investigated, by analyzing both the cells and culture media, using high-resolution NMR in conjunction with multivariate statistical methods. Upon treatment with USPIO, macrophage cells showed a significant decrease in the levels of triglycerides, essential amino acids such as valine, isoleucine, and choline metabolites together with an increase of glycerophospholipids, tyrosine, phenylalanine, lysine, glycine, and glutamate. Such cellular responses to USPIO were also detectable in compositional changes of cell media, showing an obvious depletion of the primary nutrition molecules, such as glucose and amino acids and the production of end-products of glycolysis, such as pyruvate, acetate, and lactate and intermediates of TCA cycle such as succinate and citrate. At 48 h treatment, there was a differential response to incubation with USPIO in both cell metabonome and medium components, indicating that USPIO are phagocytosed and released by macrophages. Furthermore, information on cell membrane modification can be derived from the changes in choline-like metabolites. These results not only suggest that NMR-based metabonomic methods have sufficient sensitivity to identify the metabolic consequences of murine RAW264.7 macrophage-like cell line response to USPIO in vitro, but also provide useful information on the effects of USPIO on cellular metabolism.

In vivo assessment of experimental neonatal excitotoxic brain lesion with USPIO-enhanced MR imaging

To assess the feasibility of magnetic resonance imaging (MRI) enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) for assessing excitotoxic brain lesions in an experimental model of neonatal periventricular white matter (PWM) lesions. Brain lesions were induced by intracerebral injection of ibotenate in 14 newborn rats. Pre- and post-USPIO T2-weighted MRI was performed in seven of them (group A) and in five control newborns (group C). In seven newborns with induced cerebral lesions, USPIO-enhanced MRI was not performed (group B). We compared the signal intensity of the lesion to the contralateral unaffected brain (lesion-to-brain contrast, LBC) and the lesion signal-to-noise ratio (SNR) before and after USPIO injection. MR imaging was correlated with histology. USPIO injection significantly (P<0.05) decreased LBC and SNR of brain lesion but induced no changes in normal controls. The densities of macrophages and iron-laden cells were higher on the lesion side than on the contralateral side (P<0.05). Neither lesion size nor the surrounding macrophage infiltrate was significantly different between groups A and B. Post-USPIO T2-weighted MRI demonstrated negative enhancement of neonatal excitotoxic brain lesion. USPIO injection does not appear to exacerbate brain lesions.

Ultrasmall particle of iron oxide—RGD peptidomimetic conjugate: synthesis and characterisation

Ultrasmall particles of iron oxide (USPIOs) coated with 3,3′-bis(phosphonate)propionic acid were covalently coupled to a home-made Arg-Gly-Asp (RGD) peptidomimetic molecule via a short oligoethyleneglycol (OEG) spacer. The conjugation rate was measured by X-ray photoelectron spectroscopy (XPS). The particle size and magnetic characteristics were kept. Our novel conjugate targeted efficiently Jurkat cells (increase of 229% vs the control).

Magnetic resonance lymphography in gynaecological malignancies

Following the submission of this article to Cancer Imaging, unfortunately the European manufacturer of ferumoxtran-10 (Guerbet) has withdrawn the product pending further phase III studies. This is secondary to the view of the Committee for Medicinal Products for Human Use that the phase III data did not provide adequate statistical demonstration of the product's efficacy.Magnetic resonance lymphography holds much promise for the non-invasive evaluation of lymph nodes. The technique utilizes ultrasmall superparamagnetic particles of iron oxide and has been shown to be highly sensitive and specific in the diagnosis of malignant lymph nodes. This article reviews the technique and the performance of magnetic resonance lymphography in studies to date; alternative newer methods of nodal assessment such as fluorodeoxyglucose-positron emission tomography/computed tomography and diffusion-weighted magnetic resonance imaging are also discussed, with emphasis on gynaecological malignancies.

Temporal and noninvasive monitoring of inflammatory‐cell infiltration to myocardial infarction sites using micrometer‐sized iron oxide particles

Micrometer-sized iron oxide particles (MPIO) are a more sensitive MRI contrast agent for tracking cell migration compared to ultrasmall iron oxide particles. This study investigated the temporal relationship between inflammation and tissue remodeling due to myocardial infarction (MI) using MPIO-enhanced MRI. C57Bl/6 mice received an intravenous MPIO injection for cell labeling, followed by a surgically induced MI seven days later (n=7). For controls, two groups underwent either sham-operated surgery without inducing an MI post-MPIO injection (n=7) or MI surgery without MPIO injection (n=6). The MRIs performed post-MI showed significant signal attenuation around the MI site for the mice that received an intravenous MPIO injection for cell labeling, followed by a surgically induced MI seven days later, compared to the two control groups (P<0.01). The findings suggested that the prelabeled inflammatory cells mobilized and infiltrated into the MI site. Furthermore, the linear regression of contrast-to-noise ratio at the MI site and left ventricular ejection function suggested a positive correlation between the labeled inflammatory cell infiltration and cardiac function attenuation during post-MI remodeling (r2=0.98). In conclusion, this study demonstrated an MRI technique for noninvasively and temporally monitoring inflammatory cell migration into the myocardium while potentially providing additional insight concerning the pathologic progression of a myocardial infarction.

High Resolution Ultra High Field Magnetic Resonance Imaging of Glioma Microvascularity and Hypoxia Using Ultra-Small Particles of Iron Oxide

This study assessed whether ultra-small particles of iron oxide (USPIO) intravascular contrast agent could enhance visualization of tumor microvascularity in F98 glioma bearing rats by means of ultra high field (UHF) high-resolution gradient echo (GRE) magnetic resonance imaging (MRI). In an effort to explain differences in visualization of microvascularity before and after USPIO administration, hypoxia and vessel diameters were assessed on corresponding histopathologic sections. F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Based on clinical criteria, rats were imaged 1 to 2 days before their death with and without USPIO contrast on an 8 Tesla MRI. To identify hypoxic regions of the brain tumor by immunohistochemical staining, a subset of animals also received a nitroimidazole-based hypoxia marker, EF5, before euthanasia. These sections then were compared with noncontrast enhanced MR images. The relative caliber of tumor microvasculature, compared with that of normal brain, was analyzed in a third group of animals. After USPIO administration, UHF high-resolution GRE MRI consistently predicted increased microvascular density relative to normal gray matter when correlated with histopathology. The in-plane visibility of glioma microvascularity in 22 rats increased by an average of 115% and signal intensity within the tumor decreased by 13% relative to normal brain. Tumor microvascularity identified on noncontrast MR images matched hypoxic regions identified by immunohistochemical staining with a sensitivity of 83% and specificity of 89%. UHF GRE MRI was able to resolve microvessels less than 20 micro in diameter, although differences in tumor vessel size did not consistently account for differences in visualization of microvascularity. USPIO administration significantly enhanced visualization of tumor microvascularity on gradient echo 8 T MRI and significantly improved visualization of tumor microvascularity. Microvascularity identified on precontrast images is suspected to be partly associated with hypoxia.

In Vivo Detection of Inflammation Using Pegylated Iron Oxide Particles Targeted at E-Selectin

Ultrasmall particles of iron oxide (USPIO) possess superparamagnetic properties and are used as negative contrast agent in magnetic resonance imaging (MRI) because of their strong T(2) and T(2)* effects. Besides this method, electron paramagnetic resonance (EPR) offers the unique capability to quantify these particles. The objective of this study was to evaluate a molecular marker for non invasive diagnosis and monitoring of inflammation. During inflammation cell adhesion molecules such as E-selectin are expressed on the endothelial cell surface. An E-selectin ligand was coupled to pegylated USPIO particles. Inflammation was induced by intramuscular injection of Freund's Complete Adjuvant in male NMRI mice. After intravenous injection of grafted or ungrafted USPIO particles, iron concentration in inflamed muscles was quantified ex vivo by X-band EPR. Particle accumulation was also assessed in vivo by L-Band EPR, as well as by T(2)-weighted MRI. We determined the mean iron oxide concentration in inflamed muscles after injection of grafted or ungrafted UPSIO particles, which was 0.8% and 0.4% of the initially injected dose, respectively. By L-band EPR, we observed that the concentration of the grafted USPIO particles in inflamed muscles was twice higher than for the ungrafted particles. Using MRI experiments, a higher signal loss was clearly observed in the inflamed muscle when grafted particles were injected in comparison with the ungrafted particles. Even taking into account a non specific accumulation of iron oxides, the targeting of USPIO particles with E-selectin ligands significantly improved the sensitivity of detection of inflamed tissues.

Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)‐enhanced MRI to demonstrate diffuse inflammation in the normal‐appearing white matter (NAWM) of multiple sclerosis (MS) patients: An exploratory study

To explore ultrasmall superparamagnetic particles of iron oxide (USPIO) as a marker for diffuse inflammation in multiple sclerosis (MS) normal-appearing white matter (NAWM), using quantitative MRI. Disease activity in the NAWM of MS patients partly explains why MRI lesion burden correlates only moderately with disability. USPIO have been shown to visualize the cellular component of inflammation in focal MS lesions. In this study, we aimed to explore USPIO as a marker for the more diffuse inflammation in MS NAWM, using quantitative MRI. In this prospective MRI study, 16 MS patients (eight relapsing-remitting MS [RRMS] and eight primary-progressive MS [PPMS] cases) and five healthy control (HC) subjects were included. Using a flip-angle (FA) array, B1-corrected T1 maps were generated before and 24 hours after USPIO (SHU555C) injection. White-matter (WM) T1 histogram and region-of-interest (ROI) characteristics were compared between both time points using Wilcoxon signed-rank test. Both NAWM ROI and histogram analyses showed T1 shortening after USPIO injection in MS patients (P < 0.01), but not in HCs (P = 0.68). This exploratory study suggests that USPIO-enhanced MRI may be a new potential marker for subtle inflammatory activity in MS NAWM. Further studies should focus on relating diffuse inflammation to clinical disease activity and treatment efficacy.

Nanoparticles in rectal cancer imaging

Nanoparticles have been designed as novel contrast media for the evaluation of diseases. Ultrasmall iron oxide particles (USPIO) is a novel nanoparticle contrast medium, which is currently being evaluated as an MR lymphographic agent for the assessment of tumor spread to lymph nodes. Nodal disease is an independent poor prognostic indicator in patients with rectal cancer. Accurate pre-operative MR identification of patients with nodal disease and other adverse features can prompt the use of chemoradiation to downsize and downstage the disease, with the aim of reducing the long term risk of local and distant recurrence. In this article, we discuss the challenges to accurate nodal staging of patients with rectal cancer, and demonstrate how USPIO may be applied to rectal cancer imaging to identify nodal involvement.

Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?

Gadolinium (Gd) based contrast agents (GBCAs) in magnetic resonance imaging (MRI) are used in daily clinical practice and appear safe in most patients; however, nephrogenic systemic fibrosis (NSF) is a recently recognized severe complication associated with GBCAs. It affects primarily patients with renal disease, such as stage 4 or 5 chronic kidney disease (CKD; glomerular filtration rate <30 ml/min per 1.73 m(2)), acute kidney injury, or kidney and liver transplant recipients with kidney dysfunction. Contrast-enhanced MRI and computed tomography (CT) scans provide important clinical information and influence patient management. An alternative contrast agent is needed to obtain adequate imaging results while avoiding the risk of NSF in this vulnerable patient group. One potential alternative is ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, which provide enhancement characteristics similar to GBCAs. We review our experience in approximately 150 patients on the potential benefits of the USPIOs ferumoxtran-10 and ferumoxytol. We focus on central nervous system (CNS) MRI but also review imaging of other vascular beds. Safety studies, including USPIO administration (ferumoxytol) as iron supplement therapy in CKD patients on and not on dialysis, suggest that decreased kidney function does not alter the safety profile. We conclude that for both CNS MR imaging and MR angiography, USPIO agents like ferumoxytol are a viable option for patients at risk for NSF.

Combined Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced and Diffusion-Weighted Magnetic Resonance Imaging Reliably Detect Pelvic Lymph Node Metastases in Normal-Sized Nodes of Bladder and Prostate Cancer Patients

BackgroundLymph node staging of bladder or prostate cancer using conventional imaging is limited. Newer approaches such as ultrasmall superparamagnetic particles of iron oxide (USPIO) and diffusion-weighted magnetic resonance imaging (DW-MRI) have inconsistent diagnostic accuracy and are difficult to interpret. ObjectiveTo assess whether combined USPIO and DW-MRI (USPIO–DW-MRI) improves staging of normal-sized lymph nodes in bladder and/or prostate cancer patients. Design, setting, and participantsTwenty-one consecutive patients with bladder and/or prostate cancer were enrolled between May and October 2008. One patient was excluded secondary to bone metastases detected on DW-MRI with subsequent abstention from surgery. InterventionPatients preoperatively underwent 3-T MRI before and after administration of lymphotropic USPIO using conventional MRI sequences combined with DW-MRI. Surgery consisted of extended pelvic lymphadenectomy and resection of primary tumors. MeasurementsDiagnostic accuracies of the new combined USPIO–DW-MRI approach compared with the “classic” reading method evaluating USPIO images without and with DW-MRI versus histopathology were evaluated. Duration of the two reading methods was noted for each patient. Results and limitationsDiagnostic accuracy (90% per patient or per pelvic side) was comparable for the classic and the USPIO–DW-MRI reading method, while time of analysis with 80min (range 45–180min) for the classic and 13min (range 5–90min) for the USPIO–DW-MRI method was significantly shorter (p<0.0001). Interobserver agreement (three blinded readers) was high with a kappa value of 0.75 and 0.84, respectively. Histopathological analysis showed metastases in 26 of 802 analyzed lymph nodes (3.2%). Of these, 24 nodes (92%) were correctly diagnosed as positive on USPIO–DW-MRI. In two patients, one micrometastasis each (1.0×0.2mm; 0.7×0.4mm) was missed in all imaging studies. ConclusionsUSPIO–DW-MRI is a fast and accurate method for detecting pelvic lymph node metastases, even in normal-sized nodes of bladder or prostate cancer patients.

Magnetic labeling of non‐phagocytic adherent cells with iron oxide nanoparticles: a comprehensive study

Small particles of iron oxide (SPIO) and ultrasmall particles of iron oxide (USPIO), inducing a strong negative contrast on T(2) and T(2)*-weighted MR images, are the most commonly used systems for the magnetic labeling of cultured cells and their subsequent detection by magnetic resonance imaging (MRI). The purpose of this work is to study the influence of iron incubation concentration, nanoparticle size and nanoparticle coating on the magnetic labeling and the viability of non-phagocytic adherent cells in culture. The magnetic labeling of 3T6 fibroblasts was studied by T(2)-weighted MRI at 4.7 T and by dosing-or cytochemical revealing-of iron through methods based on Perl's Prussian blue staining. Cells were incubated for 48 h with increasing iron concentrations of SPIO (25-1000 microg Fe/ml Endorem. Sinerem, a USPIO (20-40 nm) coated with neutral dextran, and Resovist (65 nm), a SPIO bearing an anionic carboxydextran coating, were compared with Endorem (dextran-coated, 80-150 nm) as magnetic tags. The iron loading of marrow stromal cell primary cultures (MSCs) isolated from rat femurs was compared with that of 3T6 fibroblasts. The SPIO-labeling of cells with Endorem was found to be dependent on the iron incubation concentration. MSCs, more sparsely distributed in the culture, exhibited higher iron contents than more densely populated 3T6 fibroblast cultures. A larger iron loading was achieved with Resovist than with Endorem, which in turn was more efficient than Sinerem as a magnetic tag. The magnetic labeling of cultured non-phagocytic adherent cells with iron oxide nanoparticles was thus found to be dependent on the relative concentration of the magnetic tag and of the cells in culture, on the nanoparticle size, and on the coating type. The viability of cells, estimated by methods assessing cell membrane permeability, was not affected by magnetic labeling in the conditions used in this work.